The invention relates to a photodynamic therapy (PDT) or process, and more particularly to a photodynamic therapy or process utilizing a photosensitive material and pyrrolnitrin for in vitro and in vivo cellular and acellular organism eradication. The invention also relates to photodynamic eradication of bacteria, fungal, and viral wound infections and sterilization of tissue using a photosensitive material, such as methylene blue, methylene green, or toluidene blue, pyrrolnitrin, and a surfactant material, such as polymyxin B, SDS, cetrimide, or benzalkonium chloride. Additionally, the invention relates to photodynamic eradication of cancer cells, such as present within a tumor, by PDT in conjunction with a photosensitive material and pyrrolnitrin. The present invention advantageously uses light energy in combination with a photosensitive material, pyrrolnitrin, and a surfactant material to treat both in vitro and in vivo pathogens, including cancer cells and microbiological pathogens. The invention also relates to the eradication or destruction of biofilms via a photodynamic mechanism. The invention also relates to an apparatus and method of use for eradication of biofilms on a diverse range of medical products, such as intravascular catheters, endotracheal tubes, and implants. The invention further relates to an apparatus and method of use for eradication of cellular and acellular organisms within an air filtration or air decontamination device for eliminating or reducing harmful biological elements such as viruses, bacteria, and fungus. The invention further relates to the eradication of spores in both in vivo and in vitro applications.
Abnormal cells and acellular organisms are known to selectively absorb certain dyes (photosensitive materials) delivered to a treatment site to a more pronounced extent than surrounding tissue. Once presensitized, abnormal cells or acellular organisms can be destroyed by irradiation with light of an appropriate wavelength corresponding to an absorbing wavelength of the photosensitive material, with minimal damage to surrounding normal tissue. This procedure, which is known as photodynamic therapy (PDT), has been clinically used to treat metastatic breast cancer, bladder cancer, head and neck cancers, esophageal cancer, lung cancer, and other types of malignant tumors, actinic keritosis, and macular degeneration.
PDT is generally used to treat hyperproliferating tissues, i.e. cancer, etc, by first administering a photosensitizer to the patient by a suitable route such as by intravenous [IV], intramuscular [IM], intraperitoneal [IP] injection, or oral administration, and then waiting for a predetermined period of time known to be sufficient to effect the preferential uptake and retention of the photosensitizer in the target tissue relative to the concentration of the photosensitizer in normal (non-hyperproliferating) tissues. By permitting time to elapse after systemic administration of the drug, the photosensitizer is generally localized in a variety of tissue/cell types as well as locations within the target tissue. The time for photosensitizer build-up in a target tissue varies but is in the range of 2-24 h. The resulting therapeutic response therefore generally involves a variety of cytological effects.
Photodynamic therapy (PDT) is a treatment that is based upon the differential uptake by cancerous cells of photosensitizing agents, followed by irradiation of the cells to cause a photochemical reaction that is believed to generate chemically disruptive species, such as singlet oxygen. These disruptive species in turn injure the cells through reaction with cell parts, such as cellular and nuclear membranes. Photodynamic therapy has been used successfully for treating several types of cancer cells.
Pyrrolnitrin is a known antibiotic which is particularly effective against fungal pathogens. Pyrrolnitrin is known as 3-Chloro-4-(3-chloro-2-nitrophenyl) pyrrole. Pyrrolnitrin is an antifungal antibiotic isolated from Pseudomonas pyrrocinia. Pyrrolnitrin may be biosynthesized from tryptophan. Proprietary preparations of pyrrolnitrin include MIEUTRIN and MICUTRIN. Another pyrrolnitrin containing compound is provided by Fujisawa Pharmaceutical Co., Ltd. Osaka, Japan.
Pyrrolnitrin is a phenylpyrrole derivative with strong antibiotic activity that has been shown to inhibit a broad range of fungi. Pyrrolnitrin was originally isolated from Pseudomonas pyrrocinia, but has since been isolated from Myxococcus species, Burkholdaria species, and several other Pseudomonas species such as Ps fluorescens. The compound has been reported to inhibit fungal respiratory electron transport and uncouple oxidative phosphorylation. It has also been proposed that pyrrolnitrin causes generalized lipoprotein membrane damage.
Air filtration devices and systems are known. Certain air filtration systems provide for eradication of biological pathogens using electromagnetic radiation. However, known electromagnetic radiation pathogen destruction techniques have significant limitations. For example, UV and microwave destruction approaches may only reduce the bacteria count, and not eradicate the pathogens altogether. Furthermore, bacteria may become resistant to UV eradication over relatively short periods of time. Microwave destruction is through generation of severe heat, i.e., 100 C. This modality would not be applicable as a portable biological weapon countermeasure. In comparison, photodynamic therapy antibacterial effects have demonstrated complete destruction and sterilization of highly concentrated bacterial species in vitro and therefore would appear to be superior to the above methods.
Many hospitalized patients, particularly patients in an Intensive Care Unit (xe2x80x9cICUxe2x80x9d), must be fitted with endotracheal tubes to facilitate their respiration. An endotracheal tube is an elongate, semi-rigid lumen which is inserted into a patient""s nose or throat and projects down into airflow communication with the patient""s respiratory system. As such, the patient either directly, or with the aid of a respiratory unit, is able to breathe more effectively through the endotracheal tube. Endotracheal tubes may remain in place within a patient for an extended period of time, e.g. up to a 14 day period. Biofilm contamination of endotracheal tubes within intubated patients may lead to an increased rate of infection, particularly pneumonia. An effective apparatus and method of use for eradication of biofilm organism on endotracheal tubes of intubated patients is desired.
Occurrences of catheter related bloodstream infection (CRBSI) have increased in part as a result of the wide use of invasive medical devices, including intravascular catheters. CRBSI is one of the most common types of nosocomial bloodstream infection, a finding that has been attributed to the wide use of intravascular catheters in hospitalized patients. Recent interventions to control CRBSI include anticoagulant/antimicrobial lock, use of ionic silver at the insertion site, employment of an aseptic hub model, and antimicrobial impregnation of catheters.
Several factors pertaining to the pathogenesis of CRBSI have been identified. The skin and hub are the most common sources of colonization of percutaneous vascular catheters. For short-term, non-nontunneled, noncuffed catheters, the organisms migrate from the skin insertion site along the intercutaneous segment, eventually reaching the intravascular segment of the tip. For long-term catheters, the hub is a major source of colonization of the catheter lumen, which ultimately leads to bloodstream infections through luminal colonization of the intravascular segment.
The catheter surface is another factor relating to the pathogenesis of CRBSI. Organisms that adhere to the catheter surface maintain themselves by producing an xe2x80x9cextracellular slime,xe2x80x9d a substance rich in exopolysaccharides, often referred to as fibrous glycocalyx or microbial biofilm. Microorganisms bind to the surface of host proteins, such as fibrin and fibronectin, to produce biofilm. As described in more detail herein, the organisms embed themselves in the biofilm layer, often becoming more resistant to antimicrobial activity. The use of lumen flush solutions including a combination of antimicrobial agents as well as anti-coagulants is a known process. Another strategy has been to impregnate the surfaces of catheters with antimicrobial agents in order to prevent colonization and the formation of biofilm. An improved approach for prevention of intravascular catheter-related infections is desired.
A considerable amount of attention and study has been directed toward preventing colonization of bacterial and fingal organisms on the surfaces of orthopedic implants by the use of antimicrobial agents, such as antibiotics, bound to the surface of such devices. The objective of such attempts has been to produce a sufficient bacteriostatic or bactericidal action to prevent colonization. Various methods have previously been employed to coat the surfaces of medical devices with an antibiotic.
U.S. Pat. No. 4,442,133, invented by Greco et al., discloses a method to coat the surface of medical devices with antibiotics involving first coating the selected surfaces with benzalkonium chloride followed by ionic bonding of the antibiotic composition. Applicant incorporates by reference herein the teachings of U.S. Pat. No. 4,442,133.
U.S. Pat. No. 4,879,135, invented by Greco et al., discloses surface modification of surgical implants by binding of drugs which, after implantation, are slowly released. More particularly, the invention relates to improved surgical implants having sustained, localized delivery of pharmacological agents such as extended antibiotic activity or reduced thrombogenicity, and methods for producing same. The surface modification of surgical implants by the adhesion thereto of pharmacological agents for the purpose of minimizing infection and prosthesis rejection is well-known and has generated broad interest for some time. Applicant incorporates by reference herein the teachings of U.S. Pat. No. 4,879,135.
Many different approaches have been taken including those disclosed in U.S. Pat. Nos. 4,563,485; 4,581,028; 5,707,366; and 4,612,337, each being incorporated by reference herein.
A biofilm is an accumulation of microorganisms including bacteria, flingi and viruses that are embedded in a polysaccharide matrix and adhere to solid biologic and non-biologic surfaces. Biofilms are medically important as they may account for a majority of microbial infections in the body. Biofilms account for many of the infections of the oral cavity, middle ear, indwelling catheters and tracheal and ventilator tubing. The National Institutes of Health estimates that the formation of biofilms on heart valves, hip and other prostheses, catheters, intrauterine devices, airway and water lines and contact lenses has become a $20 billion dollar health problem in the United States. A treatment apparatus and protocol for the reduction and/or eradication of biofilms is another aspect of the present invention.
Biofilms are remarkably resistant to treatment with conventional topical and intravenous antimicrobial agents. The Center for Biofilm Engineering at Montana State University has reported that biofilms may require 100 to 1,000 times the standard concentration of an antibiotic to control a biofilm infection. This is thought to be due to the antibiotic""s inability to penetrate the polysaccharide coating of the biofilm. Even more concerning is that biofilms increase the opportunity for gene transfer due to the commingling of microorganisms. Such gene transfer may convert a previous avirulent commensal organism into a highly virulent and possibly antibiotic resistant organism.
Bacteria embedded within biofilms are also resistant to both immunological and non-specific defense mechanisms of the body. Bacterial contact with a solid surface triggers the expression of a panel of bacterial enzymes that cause the formation of polysaccharides that promote colonization and protection of the bacteria. The polysaccharide structure of biofilms is such that immune responses may be directed only at those antigens found on the outer surface of the biofilm and antibodies and other serum or salivary proteins often fail to penetrate into the biofilm. Also, phagocytes may be effectively prevented from engulfing a bacterium growing within a complex polysaccharide matrix attached to a solid surface.
Nosocomial pneumonia is the most prevalent infection in patients who are mechanically ventilated. It is the leading contributor to mortality in patients, accounting for 50% of deaths in patients with hospital acquired infections. The endotracheal tubes (ET) and tracheostomy tubes have long been recognized as a risk factor for nosocomial pneumonia since they bypass host defenses allowing bacteria direct access to the lungs. These tubes are commonly made of polyvinyl chloride, a surface on which local bacteria colonize rapidly to form an adhesive polysaccharide glycocalyx layer. This glycocalyx layer protects bacterial colonies from both natural and pharmacologic antibacterial agents, in effect increasing the virulence of the bacterial species in the intubated host. This phenomenon of biofilm formation has been demonstrated to occur on ET tubes and subsequent dislodgement of biofilm protected bacteria in the lungs by a suction catheter is considered to be a significant factor in the pathogenesis of nosocomial pneumonia. Indeed, in a study of biofilm formation in endotracheal tubes, microbial biofilm was identified by surface electron microscopy in 29 of 30 endotracheal tubes examined. Interestingly, there was no biofilm formation on the outer surface of the ET tube. Biofilm formed exclusively on the luminal surface of all tubes regardless of whether the patients had received broad spectrum antibiotics and was most prevalent around the side hole of the tip region. ET tubes obtained within 24 hours of placement showed large areas of surface activity with adherent bacteria in a diffuse pattern indicating initial colonization of the ET tube. The surface of tubes in place for longer periods had a profuse microbial biofilm. In some instances a large mass of matrix enclosed bacterial cells appeared to project from the confluent accretion on the luminal surface of the ET tube in such a manner that it could be dislodged readily and aspirated into the lower respiratory tract. Pseudomonas species, Staphylococcus aureus, and enteric aerobic bacteria including E. coli, were the most frequently isolated pathogens in the ET tubes in patients that did not receive broad spectrum antibiotics. These also are the pathogenic bacteria most commonly found in nosocomial pneumonia. In patients that received broad spectrum antibiotics yeast species and Streptococcus species were more common. Evaluations have been made into the relationship of biofilm formation in endotracheal tubes and distant colonization of the pulmonary tree. These evaluations have demonstrated that bacteria from the endotracheal tube biofilm were capable of being cultured from the moisture exchanger and the ventilator tubing up to 45 cm from the tip of the endotracheal tube. Furthermore they demonstrated that contamination of the tracheal tube biofilm with a patient""s own gastrointestinal flora provides a mechanism for initial and repeated lung colonization and secondary pneumonia. These life threatening pulmonary infections are perpetuated by microbiological seeding from the tracheostomy and endotracheal tube biofilms and become difficult to treat due to the propensity of the biofilm microorganisms to develop antibiotic resistance. Biofilm contamination of endotracheal tubes within intubated patients may lead to infections or other complications as a result of biofilm organisms.
Catheters used for abdominal cavity tubing drainage bags and various connectors are also common sources of infection. In particular, a high percentage of patients who require long-term urinary catheters develop chronic urinary tract infections. Such patients are at risk of developing bacteremia or chronic pyelonephritis, condition of high morbidity and mortality. Many different medical articles may lead to infection when in contact with a body tissue or fluid. Exemplary of such articles are vascular access (arterial and venous) catheters, introducers, vascular grafts, urinary catheters and associated articles, such as drainage bags and connectors, and abdominal cavity drainage tubing, bags and connectors. A novel apparatus and method of infection prevention for such medical articles is particularly desired.
The present invention is directed to a photodynamic therapy utilizing a pyrrolnitrin. In particular, a photodynamic therapy of the present invention is particularly adapted for treatment of fungi, bacteria, cancer cells, and other cellular and acellular organisms. One particular fungi group particularly responsive to photodynamic therapy according to the present invention is the Aspergillus group. Yet another fungi responsive to this PDT is Candida albicans. In one embodiment of the present invention, an air filtration device is utilized to eradicate airborne pathogens.
The present invention also provides a method of photoeradication of cells and acellular organisms, such as during an in vitro or in vivo disinfection or sterilization procedure, or for cancer cell or acellular organism eradication. In one embodiment, the method utilizes a combination of a photosensitive material, pyrrolnitrin, and a chemical agent, such as a surfactant material, in a solution. The invention additionally provides a method of dispensing a combined solution at or near a cell site and subsequently irradiating the cell site with light at a wavelength absorbed by the photosensitive material. The invention also relates to an apparatus or kit assembly including a photosensitive material, pyrrolnitrin, and/or a surfactant, such as cetrimide, SDS, ARGUARD, or benzalkonium chloride. Yet another aspect of the present invention is the eradication or destruction of biofilms via a photodynamic mechanism.
The invention also relates to a use of a photosensitizing material, such as methylene blue, methylene green, or toluidene blue, in combination with pyrrolnitrin, and a surfactant compound, such as polymyxin B, SDS, ARGUARD, cetrimide or benzalkonium chloride, in a PDT treatment protocol against bacterial, fungal, acellular organism infections, and/or for cancer cell photoeradication. A treatment device is configured to deliver light energy to the area of infection or cancer cell activity at wavelengths ranging from about 450 nm to about 850 nm; provide a dosage rate ranging from about 0 to about 150 mw/cm2; and provide a light dose ranging from 0 to about 300 J/cm2.
The use of a photosensitive material, such as methylene blue, methylene green, or toluidene blue, combined with pyrrolnitrin, and optionally combined with a surfactant material, such as SDS, polymyxin B, cetrimide or benzalkonium chloride, in a photodynamic therapy advantageously acts as a broad spectrum antimicrobial, i.e., antibacterial, antiviral, sporicidal, and/or antifungal agent. PDT utilizing the photosensitizer/pyrrolnitrin/surfactant combination may occur, for example, before a surgical operation. The present invention advantageously results in the destruction of gram positive and gram negative bacteria, fungi, viruses, and spores. Importantly, the present invention acts to destroy antibiotic resistant bacteria and fungi as it utilizes a different destruction mechanism than antibiotics.
The invention also relates to a method of treating an infection including identifying an in vitro or in vivo area of infection; applying or dispensing a concentration including a photosensitive material, such as methylene blue, methylene green, or toluidene blue, pyrrolnitrin, and optionally a surfactant, such as polymyxin B, SDS, cetrimide or benzalkonium chloride, to the area of infection; and exposing the area of infection with a light having a light wavelength, light dosage and a light dosage rate. For toluidene blue, the light wavelength may range from about 560 nm to about 680 nm. For methylene blue, the wavelength may range from about 600 nm to about 670 nm. For methylene green, the wavelength may range from about 600 nm to about 670 nm. The light dosage may range from about 10 J/cm2 to about 60 J/cm2. The light dosage rate may range from about 50 mw/cm2 to about 150 mw/cm2. The concentration for methylene blue, methylene green, and toluidene blue may range from about 10 xcexcg/ml to about 500 xcexcg/ml. Pyrrolnitrin may be provided in a solution having a concentration range from about 25 xcexcg/ml to about 1 g/ml or 0.001% to 5.00%. A more preferred range of pyrrolnitrin is from about 25 xcexcg/ml to 150 xcexcg/ml. For other photosensitive materials, the preferred wavelength or range may be known or available. The area of infection may include gram positive and gram negative bacteria, fungus, spores, or viruses including, but not limited to, at least one of Staphylococcus sp., Aspergillus, Candida albicans, Escherichia coli, Enterococcus sp., Streptococcus sp., Klebsiella, Serratia, Pseudomonus aeruginosa, Hemophilus influenzae, Clostridia sp., Herpes strains, or human immunodeficiency virus (HIV).
The invention also relates to a treatment kit having a solution including at least a combination of a photosensitizing material, such as methylene blue, methylene green, or toluidene blue, and pyrrolnitrin. In addition, the solution may contain a surfactant material, such as polymyxin B, SDS, cetrimide, or benzalkonium chloride. Pyrrolnitrin may be provided in a solution having a concentration range from about 25 xcexcg/ml to about 1 g/ml or 0.001% to 5.00%. A more preferred range of pyrrolnitrin is from about 25 xcexcg/ml to 150 xcexcg/ml. For polymyxin B, the concentration ranges may be from about 3 xcexcg/ml to about 500 xcexcg/ml. For SDS and cetrimide, the concentration range may be from 0.005% to 1%. For benzalkonium chloride, the concentration ranges may be from 0.001% to 1%. A particular concentration range of interest for benzalkonium chloride is from 0.005% to 0.5%. A laser light emitting treatment device may be utilized to effect the photodynamic process, including but not limited to a light source which emits at wavelengths ranging from about 450 nm to about 850 nm; providing a dosage rate ranging from about 10 mw/cm2 to about 150 mw/cm2; and providing a light dose ranging from 5 J/cm2 to about 300 J/cm2. Alternative light sources would also be practicable as appreciated by one skilled in the relevant arts, including but not limited to non-coherent light sources, such as flash bulbs and high intensity lamps.
The invention also relates to a method of treating an infection, an in vitro or in vivo sterilization procedure, or photoeradication of cancer cells, including the steps of providing one or more cells; providing a concentration of combined photosensitive material, pyrrolnitrin, and/or surfactant on or near the one or more cells; and applying a light having a wavelength ranging from about 450 nm to about 850 nm; a dosage rate ranging from about 0 to about 150 mw/cm2; and a light dose ranging from 0 to about 300 J/cm2 to the one or more cells wherein the combination of light and photosensitive material is adapted to cause photodestruction of the one or more cells. The one or more cells may be an infection caused by or associated with a bacteria, virus, or fungus. Alternatively, the one or more cells may be cancer cells. Virus infected cells may also be treated in accordance with the present invention. In such instance, a virus within the cell may be specifically eradicated without destruction of the host cell. Obligate intracellular bacterial agents, such as Chlamydia, Rickettsia, and Ehrlichia, may be treated in accordance with the present invention. Other bacteria may also be treated in accordance with the present invention. The one or more cells may be gram positive or gram negative bacteria. The photosensitive material may be methylene blue, methylene green, toluidene blue, or a combination thereof. The photosensitive material may be monomeric, dimeric, or polymeric.
Another aspect of the present invention is a photodynamic method of biofilm reduction and/or eradication on medical devices. A wide variety of medical devices may be utilized to practice aspects of the present invention. Such devices may include implants (temporary or permanent), endotracheal tubes, catheters (venous and arterial), grafts, shunts, heart valves, orthopedic prostheses, intraocular prostheses, profusion pumps, sutures, and associated articles, such as connectors and tubing. A particular aspect of the present invention is to provide an effective apparatus and method of use for eradication of biofilm organism on endotracheal tubes within intubated patients. Alternative medical devices may be processed by teachings of the present invention to photodynamically eradicate organisms upon the devices.
Methylene blue (MB) based photodynamic therapy has been demonstrated in vitro and in vivo to be effective in the photoeradication of some antibiotic resistant gram positive and gram negative bacteria. In general, methylene blue based photodynamic therapy has limited applicability toward destruction of gram negative bacteria and fungi, such as Aspergillus. Methylene blue has a very low tissue toxicity and can be administered to humans orally and intravenously in high doses without any toxic effects. Because of the known low toxicity and its present use and acceptance in medical practice as well as its high photoactive potential this photosensitive material is ideal use in accordance with the present invention for evaluation of its effect on the destruction of bacteria, viruses and fungi. The photoactive dye methylene blue belongs to the phenothiazine class. Its bactericidal effect is related to its photodynamic properties. This dye is a single pure compound and has a strong absorption at wavelengths longer than 610 nm, where light penetration into tissue is optimal. The absorbance peaks of MB are at 611 nm and 664 nm, its optical extinction coefficient is 81600 Mxe2x88x921 cmxe2x88x921. MB has a high quantum yield of the triplet state formation (xcx9cT=0.52-0.58) and a high yield of the singlet oxygen generation (0.2 at pH 5 and 0.94 at pH 9).
The photoactivity of MB results in two types of photooxidations: (i) direct reaction between the photoexcited dye and substrate by hydrogen abstraction or electron transfer creating different active radical products; and (ii) direct reaction between the photoexcited dye in triplet state and molecular oxygen producing singlet oxygen. Both kinds of active generated products are strong oxidizers and they cause cellular damage, membrane lysis, protein inactivation and/or DNA modification.
Biofilms are resistant to topical, oral and intravenous antibiotic administration due to the polysaccharide glycocalyx formation that surrounds the bacteria. The polysaccharide coating prevents the antibiotic from penetrating into the biofilms and destroying the bacteria. Methylene blue has the potential ability to destroy biofilms as it selectively binds and penetrates polysaccharides thereby exposing the bacteria in the biofilm to the photodestructive effects of methylene blue. For this reason, methylene blue may be an ideal photosensitizer that may provide a means for the broad spectrum photoeradication of biofilms. The use of a surfactant, such as SDS or benzalkonium chloride, can act to both emulsify the biofilm and increase a membrane permeability of an acellular or cellular organism within the biofihn. The combination of a surfactant with a photosensitive material permits the photosensitive material to pass through the biofilm and acellular or cellular organism membrane, and accumulate within the acellular or cellular organism.
Another aspect of the present invention is the provision of an apparatus for eradicating airborne pathogens. A filtration device may be utilized to capture airborne biological organisms. As described herein, the filtration device may include a variety of different structures, including a small portable device to be worn by a user, to a large building air filtration device within a HVAC system. In one embodiment, photodynamic eradication of captured organisms is performed within the filtration device for eradicating the pathogen. The pathogens may include a variety of cellular and acellular organisms, including but not limited to bacteria, viruses, and fungi. Biological agents of significant concern include anthrax, tularemia, plague, Aspergillus fungi, and small pox. These biological agents should be susceptible to eradication by photodynamic therapy treatment.
Another aspect of the present invention concerns an air purification system utilizing photodynamic therapy (PDT) broad spectrum destruction of microbiological organisms. One significant application of the technology would be as a defense system against a biological weapons attack, as the broad spectrum destruction of bacteria, fungi, and viruses would offer an increased level of protection. Additional suitable applications include: temporary building environments, vehicular applications, and portable mask form.
A photodynamic air filtration device utilizing aspects of the present invention may associate pathogens with a photosensitive material and pyrrolnitrin and subsequently illuminate the pathogen/photosensitizer/pyrrolnitrin combination to achieve photodynamic eradication. In one example, a rotating filter may be used to capture pathogens for transfer into a photosensitizer/pyrrolnitrin solution. The photosensitizer solution may be selected from among a group of photosensitive materials. The pathogens and photosensitizer/pyrrolnitrin solution are subsequently illuminated by a light source, such as a VCSEL array, LED""s, a laser diode array or an incandescent bulb, to achieve the desired organism eradication. The device could be battery powered to provide field operability.
Still other objects and advantages of the present invention and methods of construction of the same will become readily apparent to those skilled in the art from the following detailed description, wherein only the preferred embodiments are shown and described, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized, the invention is capable of other and different embodiments and methods of construction, and its several details are capable of modification in various obvious respects, all without departing from the invention. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.